Table 2.

Neurochemical studies in electroconvulsive therapy

Authors	Sample	Method	Result	Limitation
				Image quality	Medication status	Control group	Follow-up
Ende et al., 2000[33]	17 patients - depressive illness	Baseline MRSI - post-ECT: After completion of at least five ECTs	No change in hippocampal NAA signals - reduced NAA - marker of neuronal death - hence, no neuronal death Significant increase in hippocampal choline signals - marker of membrane turnover - indicates mossy fiber sprouting in hippocampus	1.5 Tesla MRSI	Psychotropic medication discontinued	24 healthy controls	Last MRI 30 h-10 days after 5th or later ECT
Michael et al., 2003[34]	28 patients fulfilling DSM IV TR criteria for MDD: 13 unipolar depression and 15 bipolar depression	Left amygdalar region studied using 1.5 T steam MRSI Imaging done before and after right unilateral ECT at 2.5 ST (one case - bilateral ECT)	Before ECT, the concentration of NAA, Cho, and Cr was not statistically different between patients and controls Patients with unipolar depression showed a significantly lower concentration of Glx Successful ECT was accompanied by significant increase in NAA and Glx levels Cho and Cr increased without reaching statistical significance	1.5 Tesla MRSI	Psychotropic medication discontinued	28 healthy controls	Exact duration of follow-up not mentioned - no long-term follow-up
Michael et al., 2003[35]	12 patients with severe depression	Baseline MRSI and post-ECT MRSI (average 30 h after ECT)	Depressed patients had significantly reduced Glutamate/Glutamine - Glx levels in the DLPFC ECT responders - Marked increase in Glx levels in DLPFC ECT nonresponders - No significant increase in Glx levels in DLPFC No significant difference in NAA levels between patients and controls	1.5 Tesla MRSI	Psychotropic medication discontinued	12 age- and gender-matched healthy controls	Last MRI approximately 30 h after ECT - No long-term follow-up
Pfleiderer et al., 2003[36]	17 patients - severe recurrent unipolar depression	Medication washout period of 3-8 days 1.5 T MRSI Baseline MRSI and post-ECT MRSI (24-48 h) Unilateral ECT - 2.5 ST: 15 patients bilateral ECT - 2 ST: 2 patients	Depressed patients had significantly reduced Glx levels in the left anterior cingulate gyrus ECT responders had significant increase in Glx levels in the left anterior cingulate gyrus. ECT nonresponders - no significant increase in left anterior cingulate gyrus No significant difference in Glx levels between ECT responders and controls post-ECT - levels equalized No significant difference in levels of NAA, Cho, and Cr between patients and controls pre-ECT. No significant elevation of levels of NAA, Cho, or Cr post-ECT	1.5 Tesla MRSI	Psychotropic medication discontinued	17 age- and gender-matched healthy controls	Second MRI 24-48 h after last ECT - No long-term follow-up
Merkl et al., 2011[37]	27 patients with MDD	Right unilateral ultra-brief pulse ECT at 4 ST, 7 ST, and 10 ST - Randomized two patients received bilateral ECT 3 Tesla MRSI pre- and post-ECT		3 Tesla MRSI	Psychotropic medication continued	27 age- and gender-matched healthy controls	Second MRI after nine ECTs - No long-term follow-up
			Significant reduction in NAA and glutamate levels in the left anterior cingulum in patients
			No significant difference in Cho or Cr levels between patients and controls - both in DLPFC and anterior cingulum Significant reduction in NAA in left DLPFC post-ECT in responders Significant increase in NAA levels in the left anterior cingulum post-ECT in responders High glutamate level in the left anterior cingulum at baseline predicted greater improvement with ECT No significant correlation between glutamate levels and stimulus dosage of 4 ST, 7 ST, and 10 ST
Jorgensen et al., 2016[38]	19 patients with unipolar or bipolar severe depression	Patients assessed at three time points - T1 - before ECT: MRI, blood sample, T2 - 1 week after ECT: MRI, T3 - 4 weeks after ECT: MRI Bilateral bitemporal ECT at 1.5 ST switched to right unilateral ECT in case of severe cognitive impairment	Highly significant increase in brain volume for bilateral hippocampus and amygdala between T1 and T2 and also to a lesser extent between T1 and T3. Significant reduction in brain volume for DLPC between T1 and T3. Significant reduction volume of DLFPC post-ECT. No significant correlation between increase in volume and clinical improvement Significant decrease in FA for hippocampus between T1 and T2 and significant increase in FA for hypothalamus between T1 and T2 Also, significant reduction in MD for both hippocampus and hypothalamus between T1 and T2 No correlation between changes in FA or MD and clinical response MRSI of the left and right hippocampus showed no significant change in the concentration of NAA, Cho, and Cr between T1, T2 and T3 - however, nonsignificant increase in Cr+PCr values in the left hippocampus post-ECT Nonsignificant increase in serum BDNF levels between T1 and T2, which is lost at T3. No correlation between elevation of serum BDNF levels and clinical improvement. No correlation between serum BDNF levels and increase in regional brain volumes	3 Tesla MRSI	Psychotropic medication continued	No healthy control group	Last MRI 4 weeks after the last ECT
Njau et al., 2017[39]	50 patients with severe depression - unipolar or bipolar with a history of at least two prior episodes and at least two antidepressant trails	Patients assessed three times: T1 - 24 h prior to ECT, T2 - After 2nd ECT and T3 - 1 week after last ECT Controls scanned twice - Baseline and 4 weeks later Bilateral ECT at 1.5 ST and right unilateral ECT at 5 ST	Regions studied: dACC and sgACC and bilateral hippocampus Prior to ECT: Significantly reduced NAA and elevated Glx in the left hippocampus in patients. Significantly reduced Glx levels in sgACC in patients compared to controls Longitudinal effect of ECT: Right hippocampal NAA reduction and left hippocampal Glx reduction. dACC showed decreased NAA and increased Cr. sgACC showed increased Glx and Cr Correlation with clinical improvement - for decrease in Glx in left hippocampus and increase in Glx in sgACC Predictor of response: Higher baseline levels of NAA in dACC predicts greater response	3 Tesla MRSI	Psychotropic medication discontinued	33 age- and gender matched healthy controls	Last MRI 1 week after last ECT
Cano et al., 2017[40]	12 patients with treatment-resistant MDD	Patients were scanned four times - 24 h prior to ECT, 24 h after first ECT, 24 h after 9th ECT, and 2 weeks after completion of ECT course Controls were scanned twice - 5 weeks apart bilateral fronto-temporal ECT - stimulus dose by half-age method	Pre-ECT: No structural or metabolite concentration difference between the patient and control groups Longitudinal change: Significant increase in bilateral MTL which includes: hippocampus, parahippocampus, and amygdala and rPgACC Hippocampal NAA/Cr ratio significantly reduced after the 9th ECT and Glx/Cr ratio increased at a trend level at the same point. Cho/Cr ratio did not significantly vary between the time points Volume and metabolite correlation: Significant correlation between left hippocampal volume change and bilateral hippocampal NAA/Cr ratio change and a trend level correlation between left hippocampal volume change and bilateral hippocampal Glx/Cr ratio change - nonsignificant after Bonferroni correction for multiple comparisons Clinical correlation: Significant correlation between left MTL volume change and clinical improvement. No significant correlation between metabolite concentration change and clinical improvement	3 Tesla MRSI	Psychotropic medication continued	10 age- and gender-matched healthy controls	Last MRI 2 weeks after the last ECT

MDD – Major depressive disorder; ECTs – Electroconvulsive therapys; MRSI – Magnetic resonance spectroscopic imaging; NAA – N-acetyl aspartate; Cho – Choline-containing compounds; GLX – Glutamine and glutamate together; Cr – Creatinine; DLPFC – Dorsolateral prefrontal cortex; FA – Fractional anisotropy; MD – Mean diffusivity; BDNF – Brain-derived neurotrophic factor; ACC – Anterior cingulate cortex; dACC – Dorsal ACC; sgACC – Subgenual ACC; GMV – Gray matter volume; rPgACC – Right perigenual ACC; MTL – Medial temporal lobe; DSM IV TR – Diagnostic and Statistical Manual IV – Text Revision; ST – Seizure Threshold